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We have demonstrated that CDK5RAP3 exerts a tumour suppressor effect in gastric cancer, but its role in regulating tumour-associated macrophages (TAMs) has not yet been reported. Here, we show that CDK5RAP3 is related to the infiltration and polarization of macrophages. It inhibits the polarization of TAMs to M2 macrophages and promotes the polarization of the M1 phenotype. CDK5RAP3 reduces the recruitment of circulating monocytes to infiltrate tumour tissue by inhibiting the CCL2/CCR2 axis in gastric cancer. Blocking CCR2 reduces the growth of xenograft tumours and the infiltration of monocytes. CDK5RAP3 inhibits the nuclear transcription of NF-κB, thereby reducing the secretion of the cytokines IL4 and IL10 and blocking the polarization of M2 macrophages. In addition, the absence of CDK5RAP3 in gastric cancer cells allows macrophages to secrete more MMP2 to promote the epithelial-mesenchymal transition (EMT) process of gastric cancer cells, thereby enhancing the invasion and migration ability. Our results imply that CDK5RAP3 may be involved in the regulation of immune activity in the tumour microenvironment and is expected to become a potential immunotherapy target for gastric cancer.

BackgroundLHPP, a histidine phosphatase, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. MethodsWe obtained GC tissues and corresponding normal tissues from 8 patients and identified LHPP as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine LHPP levels in normal and GC tissues. The prognostic value of LHPP was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of LHPP in GC growth and metastasis were evaluated in vitro and in vivo. ResultsThe results showed that LHPP expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that LHPP was an independent prognostic factor and effective predictor in patients with GC. The low expression of LHPP was significantly related to the poor prognosis and chemotherapy sensitivity of gastric cancer patients. Moreover, elevated LHPP expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, the m6A modification of LHPP mRNA by METTL14 represses its expression; LHPP inhibits the phosphorylation of GSK3b through acetylation, and mediates HIF1A to inhibit glycolysis, proliferation, invasion and metastasis of gastric cancer cells. ConclusionLHPP is regulated by m6A methylation and regulates the metabolism of GC by changing the acetylation level. Thus, LHPP is a potential predictive biomarker and therapeutic target for GC.

Background: We previously demonstrated that CDK5RAP3 acts as a tumour suppressor in gastric cancer through negative regulation of the Wnt/β-catenin signalling pathway, but its function in chemotherapeutic responsiveness of gastric cancer has not been investigated. In this study, we aimed to examine the clinical significance of CDK5RAP3 to predict chemotherapeutic responsiveness in gastric cancer.Methods: A collection of 188 pairs of tumour tissue microarray specimens from Fujian Medical University were employed for the discovery set, and 310 tumour tissue samples of gastric cancer patients were employed for the internal validation set. Eight-five tumour tissue samples from Qinghai University Hospital were used as the external validation set 1. Transcriptomic and clinical data of 299 gastric cancer patients from TCGA were used as the external validation set 2. CDK5RAP3 expression, microsatellite instability (MSI) status, and tumour-infiltrating lymphocytes (TIL) were examined with immunohistochemistry. Clinical outcomes of patients were compared with Kaplan-Meier curves and the Cox model.Results: In a multi-centre evaluation, increased CDK5RAP3 indication of better prognosis depends mainly on MSI-L/MSS status or TILhigh. High CDK5RAP3 expression predicts sensitive therapeutic responsiveness to postoperative adjuvant chemotherapy in gastric cancer. In a stratification analysis based on CDK5RAP3 combined with TIL or MSI status, patients with CKD5RAP3low TILlow showed no significant difference in prognosis after receiving chemotherapy, whereas patients with CKD5RAP3low TILhigh, CKD5RAP3high TILlow, and CKD5RAP3high TILhigh had better responsiveness to chemotherapy. In addition, patients with CKD5RAP3high MSI-L/MSS status benefitted the most from adjuvant chemotherapy among all patients evaluated. Conclusions: CKD5RAP3 can be used as an effective marker to evaluate individualized chemotherapy regimens in gastric cancer patients dependent on their TIL and MSI status.

This paper adopts neutral slow passivation on the formation of cerium nitrate passivation film were studied. The electrochemical impedance spectroscopy and polarization curves of passivation film were measured after different immersion time; and analyzes the deposition of cerium passivation film on the surface by scanning electron microscopy to characterize the morphology, the surface of the XPS test.